Enzymatic Resolution of Chlorohydrins for the Synthesis of Enantiomerically Enriched 2-Vinyloxiranes

J. Adam McCubbin; Matthew L. Maddess; Mark Lautens

doi:10.1055/s-2007-1000845

LETTER

Enzymatic Resolution of Chlorohydrins for the Synthesis of Enantiomerically Enriched 2-Vinyloxiranes

J. Adam McCubbin, Matthew L. Maddess, Mark Lautens*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
Fax: +1(416)9468185; e-Mail: mlautens@chem.utoronto.ca;

Abstract

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Abstract

A series of vinylchlorohydrins are resolved by enzymatic kinetic resolution. The resulting R-alcohols, obtained in up to 99% ee, are stereoselectively converted into vinyloxiranes in high yield. The S-acetates, obtained in up to 99% ee were either deprotected to S-alcohols, or cyclized directly to vinyl oxiranes under basic conditions, with moderate to no loss in ee. The results are consistent with a racemization mechanism involving reversible migration of the acetate during deprotection.

Key words

enzymes - epoxides - kinetic resolution - alcohols - acylation

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References

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When 1a was subjected to the resolution conditions at 60 °C, no selectivity was observed.

General Procedure
A dry flask was charged with racemic alcohol 1 and vinyl acetate (1.0 mL/mmol). The resulting solution was stirred at 5, 25, or 60 °C and Amano lipase AK (3.0 mass equiv) was added as a single portion. Reaction progress was monitored by CSP-HPLC. At approximately 50% conversion, the suspension was filtered through a pad of Celite, washing with EtOAc (100 mL). The solution was concentrated in vacuo and the crude residue was purified by flash chromatography (5-10% EtOAc-hexane) to afford two fractions: (S)-2 (acetate, 1^st eluted) and (R)-1 (alcohol, 2^nd eluted). The alcohols (R)-1a-h displayed spectral properties in accordance with the racemates (see ref. 8). The acetates (S)-2a-h were characterized by ¹H and ¹³C NMR, HRMS and CSP-HPLC.
Compound (S)-2a: ¹H NMR (400 MHz, CDCl₃): δ = 7.34-7.29 (m, 2 H), 7.28-7.18 (m, 3 H), 6.67-6.61 (d, J = 15.9 Hz, 1 H), 6.12-6.05 (dd, J = 15.9, 6.1 Hz, 1 H), 5.57-5.52 (dt, J = 6.1, 6.1 Hz, 2 H), 2.06 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.0, 135.7, 134.9, 128.7, 128.5, 126.8, 123.7, 73.7, 45.6, 21.1. HRMS (EI): m/z calcd for C₁₂H₁₃ClO₂ [M⁺]: 224.0604; found: 224.0608. HPLC [CHIRALCEL OD, 1.0 mL/min, hexane-i-PrOH (98:2), 30 °C, 1 µL injection] t _R1(minor) = 12.4 min, t _R2(major) = 15.1 min; 99% ee.

The procedure reported in ref. 8 was used, and afforded the vinyloxiranes (R)-3a-f with spectral data consistent with that reported therein.

If the reaction was quenched before completion, the ee of the unreacted acetate was identical to that of the starting acetate before addition of the reducing agent. Deprotection was complete after 15 min, but the ee of the alcohol remained unchanged if left unquenched for a full hour.

<A NAME="RS06007ST-13">13</A> See for example: Lopez R. Montero E. Sanchez F. Canada J. Fernandez-Mayoralas A. J. Org. Chem. 1994, 59: 7027

General Procedure
A dry flask was charged with resolved acetate (S)-2 and heptane (10 mL/mmol). The resulting solution was cooled to -78 °C under Ar and DIBAL-H as a 1.0 M solution in heptane (1.1 equiv) was added dropwise via syringe. The solution was stirred at -78 °C for 15 min, followed by the addition of an equal volume of a sat. aq solution of Rochelle’s salt. The mixture was transferred to a separatory funnel and extracted twice with Et₂O (25 mL). The combined organic extracts were dried (MgSO₄) and concentrated in vacuo. The crude residue was purified by flash chromatography (10% EtOAc-hexane) to afford the desired alcohol (S)-1. The products displayed spectral characteristics in accord with the racemate (see ref. 8).

General Procedure
To a round-bottom flask was added resolved acetate (S)-2 and MeOH (10 mL/mmol) and the reaction vessel cooled in an ice bath. Then, K₂CO₃ (1.1 equiv) was added portionwise as a solid. The heterogeneous reaction was stirred at 0 °C and the progress monitored by TLC for the consumption of starting material. After 1 h, the reaction was quenched carefully by the addition of sat. aq NH₄Cl, and after an equal volume had been introduced the reaction mixture was concentrated, diluted with Et₂O and transferred to a separatory funnel. The organic layer was isolated, the aqueous layer extracted with Et₂O and the combined organics dried with MgSO₄, filtered, and concentrated in vacuo to afford the desired vinyloxirane (S)-3 in sufficient purity for subsequent reactions. The product displayed spectral characteristics in accord with the racemates (see ref. 8).

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The experimental details for this reaction were not included in ref. 16; however, they were obtained through personal communication with the authors.

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Alternatively, racemization could occur under certain conditions via ionization of 4a, followed by internal return.